There are many pathological conditions, particularly cancer, when aberrant tissue growth poses serious health hazard that would require rapid, selective, and effective elimination of the constituent aberrant cells. There are three major procedures in the medical practice, used alone or in combination, to accomplish this goal, i.e. surgery, radiotherapy, and chemotherapy. Each procedure, particularly when used alone, has its drawbacks. In case of cancer, a frequent problem associated with surgery is that it is often difficult to determine the tumor margin. Accordingly, the surgeon may not remove all cancer tissue thereby increasing the chances of local recurrences. Alternatively, the surgeon may remove an unnecessarily large area of uninvolved tissue. During surgery many cancer cells also disseminate into the vascular system thereby increasing the incidence of secondary cancers, particularly liver cancer [Weitz, J., Kienle, P., Lacroix, J., Willeke, F., Benner, A., Lehnert, T., Herfarth, C. and von Knebel Doeberitz, M. (1998) Dissemination of tumor cells in patients undergoing surgery for colorectal cancer. Clin. Cancer Res. 4, 343-348; Futoshi, M., Sonshin, T., Shoji, N., Keiichirou, U., Fumio, K., Kuniaki, A., Hiroyuki, S. and Takashi, A. (1999) Molecular detection of circulating cancer cells during surgery in patients with biliary-pancreatic cancer. Am. J. Surg. 177, 475-479]. Finally, in many cases the cancer is inoperable (too many tumors, inaccessible site, or risk of intervening with a vital function).
Radiotherapy, while in many cases effective, can in itself cause various cancers [Camphausen, K., Moses, M. A., Beecken, W.-D., Khan, M. K., Folkman, J. and O'Reilly, M. S. (2001) Radiation therapy to a primary tumor accelerates metastatic growth in mice. Cancer Res. 61, 2207-2211; Curtis, R. E., Boice, J. D. Jr., Stavall, M., Flannery, J. T. and Moloney, W. C. (1989) Leukemia risk following radiotherapy for breast cancer. J. Clin. Oncol. 7, 21-29; Shore, R. E. (2001) Radiation-induced skin cancer in humans. Med. Ped. Oncol. 36, 549-554; Travis, L. B., Gospodarowitz, M., Curtis, R. E., Clarke, E. A., Andersson, M., Glimelius, B., Joensuu, T., Lynch, C. F., van Leeuwen, F. E., Holowaty, E., Storm, H., Glimelius, I., Pukkala, E., Stovall, M., Fraumeni, J. F, Jr., Boice, J. D, Jr. and Gilbert, E. (2002) Lung cancer following chemotherapy and radiotherapy for Hodgkin's disease. J. Natl. Cancer Inst. 94, 182-192].
Major problems with the application of chemotherapeutic agents is that they usually do not provide a sufficient “therapeutic window”, i.e. at doses that would have optimal effects on cancer growth they almost invariably attack normal tissues as well. Another problem with chemotherapy is that cells in the same tumor usually respond to a different degree, depending on how heterogeneous the tumor is. Thus chemotherapy can gradually select for less responding cancer cell populations in the tumor. Yet another problem is that chemotherapy can also induce secondary cancers [Travis, L. B., Gospodarowitz, M., Curtis, R. E., Clarke, E. A., Andersson, M., Glimelius, B., Joensuu, T., Lynch, C. F., van Leeuwen, F. E., Holowaty, E., Storm, H., Glimelius, I., Pukkala, E., Stovall, M., Fraumeni, J. F, Jr., Boice, J. D, Jr. and Gilbert, E. (2002) Lung cancer following chemotherapy and radiotherapy for Hodgkin's disease. J. Natl. Cancer Inst. 94, 182-192].
Finally, more often than not, cancer cells develop resistance to a wide range of drugs which will eventually make chemotherapy ineffective [Volm, M. (1998) Multidrug resistance and its reversal. Anticancer Res. 18, 2905-2918]. Although some agents have been developed to reverse multidrug resistance, they almost invariably exert toxic side effects, because the proteins responsible for drug resistance are also expressed and required for the normal function of some other organs [Volm, M. (1998) Multidrug resistance and its reversal. Anticancer Res. 18, 2905-2918].
Several other procedures are presently under development or already entered the clinical practice that provides a more selective treatment of aberrant growth. An example for this new targeted approach is Gefitinib (Iressa, ZD1839) which targets the epidermal growth factor receptor that is often highly expressed in tumor cells [Wolf, M., Swaisland, H. and Averbuch, S. (2004) Development of the novel biologically targeted anticancer agent Gefinitib: Determining the optimum dose for clinical efficacy. Clin. Cancer Res. 10, 4607-4613]. However, most “targeted” treatments have a relatively limited scope, because they usually target specific antigens that may not be universally present even in the same tumor due to the heterogeneous origin of tumor cells. Presently available targeted anti-cancer molecules are not sufficiently versatile for using them against a wide variety of tumor targets. Thus, there is an urgent need for chemotherapy of wider scope that can rapidly, efficiently, and at the same time specifically kill non-normal or non-healthy cells including cancer cells. Such specific “shot-gun” approach would enhance the efficacy of surgery, radiotherapy, and chemotherapy or even may render these procedures unnecessary.